Hydroxylated alpha, beta-diphenyl-beta-hydroxy-ethylamines and the preparation thereof



Patented Apr 25, 1950 HYDROXYLATED ALPHA,BETA-DIPHENYL- BETA-HYDROXY-ETHYLAMINES AND THE PREPARATION THEREOF Warren D. McPhee, Castleton on Hudson, N. Y.,

assignor, by mesne assignments, to Winthrop- Stearns Inc., New York, N. Y., a corporation of Delaware No Drawing. Application October 18, 1945, Serial No. 623,173

This invention relates to a,s-diphenyl-B-hydroxyethylamines and salts thereof, wherein the p-phenyl nucleus is substituted with hydroxy radicals, and to methods of preparing the same.

In particular it relates to a-nhenyl-o-(e-hydroxyphenyl) -B-hyd10xyethy1amine and salts thereof, and to processes of preparing the same.

The object of this invention is to provide new compositions of matter which are therapeutically useful due to their valuable analgesic properties. A further object of this invention is to provide new medicinal preparations having analgesic action suited for treatment of humans and animals.

In general, the new compositions which are the basis of this invention are a,;3-dipheny1-B-hy droxyethylamines wherein the fi-phenyl nucleus 8 Claims. (01.260-5705) is substituted with hydroxyl radicals, having the following general formula:

In a preliminary survey Dodds, Lawson and 7' Williams [Nature 151, 614 (1943) Proc. Roy. Soc. (London), B, 132, 119 (1944)] reported that afidiphenyl-{i-hydroxyethlamine and certain homologs thereof relieve pain due to pressure on the nerves of humans with inoperable tumors. In a later note by the same workers [Nature, 154, 514 (1944)] it is stated that a,/3diphenvl-c-hydroxyethylamine and related compounds previously tested clinically are entirely devoid of analgesic activity when tested by t e electric shock method on rats. The compoundswhich had been used clinically have a specific action on nerve pressure pain, but no general analgesic effect. The series of e,B-dipheny1-p-hydroxyethylamines tested by the English workers did not, however, include those in which the a-phenyl radical is unsubstituted and in which the B-phenyl radical is substituted with one or more hydroxyl groups.

I have discovered that a-phenyl-p-(hydroxyphenyl)- 3-hydroxyethylamines and salts thereof produce general analgesia in humans and animals. This discovery is surprising in light of the disclosure of Dodds, Lawson and Williams [Nature, 154 514 (1944)] that p-diphenyl-fi-hydroxyethylamine and related compounds have no universal analgesic action and cannot be used generally as substitutes for morphine.

The amines which are the basis of this invention maybe employed either in the form of the free bases or in the form of salts. For parenteral administration it is desirable that the compositions be soluble in water. For this purpose the hydrochlorides of the bases are suitable. Other acids may be used in preparing salts of the amines, among them being sulfuric, citric, lactic and tartaric. The term salts is used herein to include any salt of an a',B-diphenyl-B-hydroxyethylamine, wherein the fi-phenyl nucleus is hydroxylated, with any acid, the anion of which is tolerated in therapeutic dosages.

The method of preparing a-phenyl-fl-hydroxyphenyl--hydroxyethy1amines is outlined in the following series of equations and illustrated in the appended examples. It will be apparent to those skilled in the art that a number of other substituted phenols may be used in the reaction without departing from the spirit and scope of my invention.

HO- ---COCH RONO CQH5CHQO- COCH:

H: CaHgCHaO- 000- ---b l! Pd NOH r-Q) OH NH:

R=lower alkyl The following examples are merely illustrative and in no way limit my invention.

Example 1 (Afflenzyl p-hydroryphenyl ketone.-This is prepared by heating and stirring 12.2 g. (0.13

mole) of phenol,- 3'? g. (0.28 mole) of aluminum chloride, 100 cc. of nitrobenzene and 17.2 cc. (0.13 mole) ofuphenylacetylchloride at -90 C. for ninety minutes. The cooled reaction mixture is poured into 300 cc. of ice water containing 10 cc. .of concentrated hydrochloric acid. The product is isolated by extraction with ether followed by extraction with dilute sodium. hydroxide solution and acidification. The yield is 16.8 g. (61%) of tan solid, M. P. 139-142 C. with sintering from 132 C. ECf. Weise, Monatsh., 26, 986 (1905)] (B) Benzyl p-beneyloxyphenyl ketone.-164 g. (0.774 mole) of the product shown in Example 1(A) is benzylated by refluxing and stirring with 98 cc. (0.852 mole) of benzyl chloride, 57.6 g. (0.542 mole) of sodium carbonate, 6.44 ,g. (0.039 mole) ofpotassium iodide and 800 cc. of 95% a1- cohol for eight hours. On cooling, the mass solidifies. The product is filtered, washed with water and alcohol and dried. The yield is 205 g. (88%) of ketone, M. P. 136-137"C. Calculated for C21H1a022C, 83.42; H, 6.00. Found C, 83.66; H, 5.86.

(C) a-isonitrosobenzyl p-ben'zyloatyphenyl Icetone.--A suspension of g. of the ketone 'prepared Example 1(B) is nitrosated in 200 cc. of refluxing dry ether by slow addition of a large excess of amyl nitrite (10 cc.) and dry, gaseous, hydrogen chloride. The nitrosated product is soluble in ether and is readily separated from the starting material by filtration. The filtrate is treated with two volumes of petroleum ether of B. P. -90 C. and 5.5g. (51% yield) of the isonitrosoketone crystallizes out; M. P. I26' 127 C., with sintering from 122 C. Recrystallization .from benzene raises the M. P. to 131-132 C1.

Calculated for Ca1H1'l03N: N, 4.23. Found N. 4.21.

(D) a-PhQflZ/Z-fi- (st-hydinryphenyl) -;3hZ/d70,1tg ethylamine hydrochloride.-A suspension of 23 g. (0.07 mole) of the isonitroso ketone'in 150 cc. of

methanol is reduced in the) presence of palladiumon-charcoal catalyst at 55 C. and 50 lbs/sq. in.

culated for CriHrisOzNClt N, 5.27. Found: N, 5.00.

(E) a PhenyZ-fl-4 hydromgphengl-fl-hydromy ethylamine may be obtained from its hydrochloride by treating an aqueoussolution of its hydrochloride with dilute aqueous ammonia until basic and removing the precipitate. Recrystallization from methanol' ields the free base, having a M. P. greater than 235 C;

Ewample' 2 (A) Beneyl 3,4-dihydroxyp'henyl Icetone.-A

mixture of g. (I mole) of catechol, '136 g. (1 mole) of phenylacetic acid, and 101 g. (0.66 mole) of phosphorus oxychloride is stirred for two hours at 90l00 C. at the end of which time a thick, dark brown paste results and stirring is difiicult. Two hundred and fifty grams of water is introduced and the mixture refluxed for an hour. Upon cooling, the: red -brown oil forms a redorange solid. This is washed with hot benzene and dried. The yield is 134 g. (59%); M. P. 168- 170 C., with Sinteringfrom 162 Ci [-C f. Finzi, Monat'sha, 26, 11 33 1905')"] (B) Benzyi 3,4 dibenzyloxyphefiy'l Icetone;-- benzylation isc'arried outasin Example 1(3) using" g. (0.57 mole) of the Llihydroxy keton'e, 159 g. ("1.25 mole) of beriz'yl chloride, 170 g."(-1.6 mole) of sodium carbonate; 4.7 g. (0.03 mole) of potassium iodide, and 500 ccuof alcohol. Recrystallization from alcohol affords-153 g. (66% yield) of product, M. P. 91.593-'C A second recrystallization gives M. P. 92.5-93 C- Calculated for (52813124031 C, 82.33; H, 5.92. Found: C, 82.39; H, 5.83.

r (C) a-lsonitrosobenzyl 3,4 dibenzyloxyphenyl lcetoneL- -The nitrosatio'n is similar to thepreviou's drorcyethylamme hydrochloride.-Twelve grams (0.0275 mole) of the isonitroso ketone is reduced in cc. of 67% aqueous methanol containing an equivalent of hydrochloric acid, in the presence of palladium-on-charcoal catalyst. Debenzylation and reduction of the isonitrosogroup proceeds at room temperature. The ketone is reduced at 55 C., the total time being ten hours. The solution is filtered and evaporated to dryness. Recrystallization from benzene-ethanol yields g. (43%) of white crystals, M. P. 172 173" C. (decomp). Calculated for 014111603201: N, 4.97. Found: N, 4.89.

What I claim is 1. An afi diphenyl 13- hydroxyethylamine wherein the fi-phenyl nucleus contains one to two hydroxyl groups, and salts thereof.

2. An a-phenyl-5-rnonohydroxyphenyl fl hydroxyethylamine and salts thereof.

3. a-Phenyl-c-4-hydroxyphenyl ,8 hydroxyethylamine and salts thereof.

4. An a-phenyl-B-dihydroxyphenyl-(Lhydr'oxye'thylamine and salts thereof.

tl-roxyethylamine hydrochloride.

8. a-Phenyl-c-4-hydroxyphenyl' ,8 hydroxyethylamine hydrochloride.

7. A process of preparing an a-phenyl-fi-hydroxyphenyl-fi-hydroxyethylamine which comprises catalyt-icall-y reducing an alpha-isonitrosobenzyl benzyloxyphenyl ketone.

8. A- process of preparing a-phenyl-B-i-hydroxyphenyl-p-hydroxyethylamine which comprises catalyticall'y hydrogenat'ng alpha--ison-itrosobenzyl' 4-benzyloxyphenyl ketone.

WARREN D. McPHEE.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATE-S PATENTS Number Name Date 1,965,502 Legerlotz July 3, 1934 FOREIGN PATENTS Number Country Date 

1. AN A,B-DIPHENYL - B - HYDROXYETHYLAMINE WHEREIN THE B-PHENYL NUCLEUS CONTAINS ONE TO TWO HYDROXYL GROUPS, AND SALTS THEREOF. 